Honors Cup Synthetic Proposal (230 V- Tu PM- W08)
Section: 230
Group Members: Christina Suh, Mark Pressprich, Michelle Robinette
Title: Synthesis of luminol (5-amino-2,3-dihydro-1,4-phthalazinedione) from 1-nitronaphthalene
Introduction:
Marked by the bright blue light it emits when oxidized, luminol is one of the most well-known and
widely-used chemiluminscent substances. While luminol is often used by biologists to confirm
trace compounds, perhaps its most commonly recognized use is in the field of police work. The
necessity of a catalyst in the oxidation of luminol by hydrogen peroxide allows forensic
investigators to take advantage of luminol's chemilumiscence in the search for blood at crime
scenes. In this case, the iron from the hemoglobin in blood catalyzes the oxidation, providing a
quick visual "verification" of trace amounts of blood. However, this information can sometimes be
misleading, as other naturally occurring compounds can also operate as catalysts.
Overall synthetic reaction scheme:
A
NO2
B
NO2
O
OH
HNO3, CH3CN
1-nitronaphthalene
OH
cat. Ce(NH4)2(NO3)6
O
3-nitrophthalic acid
H2NNH2
X
NH2
O
NH
Pd(OAc)2/PMHS/KF
C
NO2
CH3COOH
O
NH
NH
NH
THF
O
O
luminol
3-nitrophtalhydrazide
Step
1
Step 1:
Synthetic Transformation 1:
Synthetic transformation 1:
NO2
NO2
O
OH
HNO3, CH3CN
OH
cat. Ce(NH4)2(NO3)6
1-nitronaphthalene
O
3-nitrophthalic acid
Experimental 1:
The first step of the synthesis was the solid-phase oxidation of 1-nitronaphthalene to 3nitrophthalic acid in an acidic-aqueous solution employing ammonium ceric nitrate as the catalyst.
1-nitronaphthalene (3.00 g, 17.3 mmol) was dissolved in acetonitrile (5 mL) and mixed well with
dilute nitric acid (69.2 mmol) in a 50 mL round-bottom flask. To this, 2.25 g ammonium ceric
nitrate was added. The mixture was heated under reflux for 1 hour at 90-100º C. After being cooled
to room temperature, the reaction was filtered, and the filtrate neutralized with Na2CO3 and washed
with ethyl acetate, then adjusted to a pH of 2.0 with HCl prior to extraction of the product with
methanol. 3-nitrophthalic acid was then isolated from methanol by evaporation under reduced
pressure. Experimental ratios were changed to optimal levels based on data for the catalyst of
interest in the reported synthesis, 5% CeO2/Al2O3. Reflux was added to the procedure due to the
low boiling point of acetonitrile (80º C).
Expected yield:
34.2%
1.25 g
Safety, Disposal and Green issues 1:
a) 1-nitrophthalic acid is a strong reducing agent which can be dangerous when mixed with nitric
acid.
b) Acetonitrile is highly flammable. It is toxic via skin contact, inhalation, and ingestion. As an
irritant, acetonitrile may cause serious damage to the eyes. All reactions should take place under
closed hoods, and safety glasses should be worn at all times.
c) Nitric acid is extremely toxic and corrosive. Contact with skin or eyes can cause serious burns
and permanent damage.
d) Ammonium ceric nitrate is a strong oxidant that may cause fire when in contact with combustible
material. It is a skin, eye, and respiratory irritant.
e) For 3-nitrophthalic acid, see Safety, Disposal and Green Issues 2.
The nitric acid can be disposed in acid waste. Acetonitrile should be disposed of as an ignitable
waste, as the flash point is 2º C. 1-nitrophthalic acid should be disposed of as a reducing agent, and
ammonium ceric nitrate as an oxidizing agent.
Step 2
Step 2:
Synthetic Transformation 2:
Synthetic transformation 2:
NO2
NO2
O
OH
OH
O
3-nitrophthalic acid
H2N-NH2
CH3COOH
O
NH
NH
O
3-nitrophthalhydrazide
Experimental 2: (Modernized from 1934 procedure; no open flames, no salts, no oil-bath)
In a 25 mL round-bottom flask, hydrazine (0.0055 mol or 0.176 g) and acetic acid (0.011 mol or
0.661 mL) were dissolved in 5mL of heated H2 O. The solution was then added to 3-nitrophthalic
acid (0.0055 mol or 1.16 g) in a 75 mL porcelain evaporating dish and evaporated on a hot plate.
The remaining solid was put in a 25 mL beaker and heated in sand for an hour with the
temperature maintained at 160° C. The solid was stirred to avoid caking. The product, 3nitrophthalhydrazide, was then cooled to room temperature.
Expected yield: 99.5%
1.05g
Safety, Disposal and Green Issues:
a) 3-nitrophthalic acid is an irritant. It is harmful if inhaled, ingested, or absorbed through the
skin. Safety glasses and adequate ventilation should be used.
b) Hydrazine may be an explosion hazard, especially when heated. It is a poison and likely a
human carcinogen. It is harmful if inhaled or swallowed and may cause severe skin and eye
irritation or burns. Long-term exposure may cause damage to the central nervous system, lungs,
blood, liver, or kidney. Safety glasses and gloves should be worn. It should be used with adequate
ventilation and treated as a carcinogen.
c) Acetic acid is flammable and corrosive. Concentrated acetic acid can cause serious burns, and
contact with the eyes can cause severe long-term damage. Safety glasses should be worn. Contact
with skin should be avoided.
Step3:3
Step
Synthetic Transformation 3:
Synthetic transformation 3:
NO2
NH2
O
NH
NH
O
Pd(OAc)2/PMHS/KF
NH
THF
NH
O
O
Experimental 3: (Adapted from a general procedure for the reduction of a nitro group)
A 500 mL 3 necked round-bottom flask was charged with 1 equivalent 3-nitrophtalhydrazine (.685
g, 3.31 mmol), .05 equivalents Pd(AcO)2 (.0364g, .165 mmol), 20 mL dry THF and a magnetic
stirring rod. The flask was sealed (with septa) and purged with nitrogen. While purging the flask, a
solution of 2 equivalents KF (.384 g, 6.62 mmol) dissolved in 6.6 mL degassed water was added
via syringe. 4 equivalents PMHS (.794 mL, 13.24 mmols) were added slowly dropwise via syringe.
The reaction ran for 30 minutes or until complete as judged by TLC.
Isolation:
After reaction was complete, the flask was opened to air and diluted with 20 mL diethyl ether, and
stirred for 5 minutes. The layers were separated and the aqueous layer extracted using diethyl ether.
The combined organic layers were filtered through celite (top layer) and neutral alimina (bottom
layer) in 1 cm diameter column by flushing with EtOAc. The filtrate was concentrated and subjected
to flash chromatography (silica gel, hexanes/EtOAc).
Expected yield: 89%*
.7697 g*
Safety, Disposal and Green Issues:
a) THF and dietheyl ether are known to form peroxides on contact with air, which if allowed to
evaporate can leave a mixture of highly explosive compounds. The THF and diethyl ether we have
suggested buying contain BHT to inhibit formation of these compounds. They are also an eye and
skin irritants, as well as inhalation hazards. Both THF and diethyl ether are highly flammable, and
diethyl ether is notably a large explosion hazard, since its vapors can travel considerable distant to a
flame or spark source (hot plates included).
b) Diethyl ether may be placed in a waste solvent container for disposal.
c) THF should be disposed of in a container containing no halogens, strong oxidizing or reducing
agents, or in contact with oxygen.
d) As a source of fluorine, KF should not be ingested.
*This base for experimental yield is based upon the yield for a nitro arene with a ketone group meta
to the nitro group.
Overall Budget:
Chemical
Supplier
Cost
Total
$18.90 / 100g
$43.10 / 1L
$32.10 / 1L
Amt.
Needed
3.0 g
5.0 mL
69.2 mL
1-nitronaphthalene (99%)
acetonitrile (99%)
nitric acid (solution, 1M)
Aldrich
Aldrich
Riedel-de Haën
ceric ammonium nitrate
hydrazine (anhydrous,
98%)
acetic acid (99.99%)
celite
aluminum oxide (neutral)
diethyl ether (anhydrous)
tetrahydrofuran
(anhydrous, 99.9% with
BHT as inhibitor)
poly(methylhydrosiloxane)
palladium(II) acetate
ethyl acetate
Na2CO3
methanol
hydrochloric acid
potassium fluoride
Fluka
Sigma-Aldrich
$26.50 / 100g
$54.10 / 50g
2.50 g
0.127 g
$0.66
$0.14
Sigma-Aldrich
Fluka
Sigma-Aldrich
Aldrich
Aldrich
$24.20 / 25mL
$34.80 / 1kg
$30.30 / 100g
$291.50/6L
$296.00/12L
0.661 mL
10 g
10 g
40 mL
20 mL
$0.64
$0.35
$3.03
$1.94
$0.49
Fluka
Aldrich
Sigma-Aldrich
Riedel-de Haën
Aldrich
Fluka
Sigma-Aldrich
$32.60/100mL
$40.00/500mg
$389.50/20L
$43.50/ 5L
$327.50/ 16 L
$26.90/ 1 L
$55.80/250g
0.794 mL
37.04 mg
100 mL
2 mL
20 mL
1 mL
0.384g
$0.26
$2.96
$1.95
$0.04
$0.41
$0.27
$0.08
$0.57
$0.21
$2.22
Total costs per synthesis: _____$16.22___
∗Because our expected yield for the final step is unknown, these values reflect the highest
possible amounts of reagents that may be used.
References:
Step 1:
Rajiah, T.; Chary, K. V. R.; Rao, K. S. R.; Rao, R. N.; Prasad, R. Green Chem. 2002, 4, 210-212.
Step 2:
Huntress, E. H.; Stanley, L. N.; Parker, A. S. J. Am. Chem. Soc. 1934, 56, 241-242.
Step 3:
Rahaim, R. J.; Maleczka, R. E. Org. Lett. 2005, 7, 5087-5090.